rs3176126

Variant names:

• chr20-23045634-G-A
• rs3176126
• NM_000361.3:c.*2143C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000361.3(THBD):​c.*2143C>T variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 152,264 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (21 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: THBD NM_000361.3 splice_region
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.398
• Publications: 5 publications found

Genes affected

THBD (HGNC:11784): (thrombomodulin) The protein encoded by this intronless gene is an endothelial-specific type I membrane receptor that binds thrombin. This binding results in the activation of protein C, which degrades clotting factors Va and VIIIa and reduces the amount of thrombin generated. Mutations in this gene are a cause of thromboembolic disease, also known as inherited thrombophilia. [provided by RefSeq, Jul 2008]

THBD Gene-Disease associations (from GenCC):

• atypical hemolytic-uremic syndrome with thrombomodulin anomaly

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• thrombomodulin-related bleeding disorder

  Inheritance: AR, AD, Unknown Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ENSG00000296483 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 20-23045634-G-A is Benign according to our data. Variant chr20-23045634-G-A is described in ClinVar as [Benign]. Clinvar id is 337849.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0123 (1868/152264) while in subpopulation SAS AF = 0.0193 (93/4826). AF 95% confidence interval is 0.0171. There are 21 homozygotes in GnomAd4. There are 935 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THBD	NM_000361.3	c.*2143C>T		splice_region_variant	Exon 1 of 1	ENST00000377103.3	NP_000352.1
THBD	NM_000361.3	c.*2143C>T		3_prime_UTR_variant	Exon 1 of 1	ENST00000377103.3	NP_000352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THBD	ENST00000377103.3	c.*2143C>T		splice_region_variant	Exon 1 of 1	6	NM_000361.3	ENSP00000366307.2
THBD	ENST00000377103.3	c.*2143C>T		3_prime_UTR_variant	Exon 1 of 1	6	NM_000361.3	ENSP00000366307.2
ENSG00000296483	ENST00000739851.1	n.796-3883C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1865 AN: 152146 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.0231

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.00813

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0123 AC: 1868 AN: 152264 Hom.: 21 Cov.: 33 AF XY: 0.0126 AC XY: 935 AN XY: 74450

African (AFR) AF: 0.00250 AC: 104 AN: 41548

American (AMR) AF: 0.0107 AC: 163 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.0193 AC: 93 AN: 4826

European-Finnish (FIN) AF: 0.0231 AC: 245 AN: 10594

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0179 AC: 1220 AN: 68028

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.0154 Hom.: 62

Bravo AF: 0.0106

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atypical hemolytic-uremic syndrome with thrombomodulin anomaly Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	11
DANN	Benign	0.84
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3176126; hg19: chr20-23026271;